rs61743088

Positions:

• chr6-117394232-C-G
• chr6-117394232-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001378902.1(ROS1):​c.1121G>C​(p.Gly374Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,609,766 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 4.97

Genes affected

ROS1 (HGNC:10261): (ROS proto-oncogene 1, receptor tyrosine kinase) This proto-oncogene, highly-expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011647165).
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROS1	NM_001378902.1	c.1121G>C	p.Gly374Ala	missense_variant	11/44	ENST00000368507.8	NP_001365831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROS1	ENST00000368507.8	c.1121G>C	p.Gly374Ala	missense_variant	11/44	5	NM_001378902.1	ENSP00000357493	P1
ROS1	ENST00000368508.7	c.1094G>C	p.Gly365Ala	missense_variant	10/43	1		ENSP00000357494

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00146 AC: 363 AN: 248022 Hom.: 4 AF XY: 0.00179 AC XY: 240 AN XY: 134192

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00894

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00114 AC: 1667 AN: 1457544 Hom.: 16 Cov.: 30 AF XY: 0.00144 AC XY: 1046 AN XY: 724978

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000317

Gnomad4 ASJ exome AF: 0.000269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000669

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000815 AC: 124 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74420

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00150 AC: 182

EpiCase AF: 0.000880

EpiControl AF: 0.000955

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ROS1: BS2 -

ROS1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.27	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.95	P;.
Vest4		0.27
MVP		0.65
MPC		0.21
ClinPred		0.67	D
GERP RS		5.1
Varity_R		0.23
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61743088; hg19: chr6-117715395;